Dipeptidyl peptidase-IV (DPP-IV) is a serine protease that belongs to a group of amino-dipeptidases that includes DPP-VII, DPP-VIII, DPP-IX, and fibroblast activation protein (FAP). DPP-IV, which catalyzes the release of an N-terminal dipeptide from proteins, is believed to play a role in the control of glucose metabolism. In vivo administration of synthetic inhibitors of DPP-IV prevents N-terminal degradation of the insulinotropic hormone glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) resulting in increased insulin secretion and improved glucose tolerance. Substituted aminoacetyl pyrrolidine boronic acids have been developed as inhibitors for the treatment of patients with impaired glycemic control such as Diabetes Mellitus and related conditions. Consequently, it is desirable to formulate such inhibitors as convenient-to-use solid pharmaceutical materials. Free bases and salts of many pharmaceutical compounds are such typical pharmaceutical formulations. However, the free base forms of some aminoacetyl pyrrolidine boronic acids are not stable solids, readily absorbing atmospheric moisture. In addition, some salts of these free bases are likewise not stable solids.
U.S. application Ser. No. 10/514,575, filed Nov. 15, 2004, titled “Heterocyclic Boronic Acid Compounds,” and published on Mar. 15, 2007 as US 2007/0060547, discloses a large class of pyrrolidine boronic acid compounds that inhibit dipeptidyl peptidase-IV. In addition, U.S. Provisional Application Ser. No. 11/381,085, filed May 1, 2006, titled “Pyrrolidine Compounds and Methods for Selective Inhibition of Dipeptidyl Peptidase-IV,” and published on Nov. 23, 2006 as US 2006/0264400, discloses a more specific class of pyrrolidinylaminoacetyl pyrrolidine boronic acid compounds that selectively inhibit DPP-IV. One embodiment of that invention shows particular promise as a medicament. However, although biologically effective as a free base, the free base compound is not physically or chemically stable as a solid on storage.
Therefore, there is a need for a chemically stable salt form of the compound for use in pharmaceutical formulations for treatment of malconditions wherein selective inhibition of DPP-IV is medically indicated.